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com
Open Access
To cite: Krul MMG,
Bogaard K, Knol RJJ, et al.
Coronary artery disease in
patients with atypical chest
pain with and without
diabetes mellitus assessed
with coronary CT
angiography. BMJ Open
Diabetes Research and Care
2014;2:000004. doi:10.1136/
bmjdrc-2013-000004
MMGK and KB contributed
equally.
Received 18 November 2013
Revised 26 February 2014
Accepted 26 March 2014
1
Department of Cardiology,
Medical Center Alkmaar,
Alkmaar, The Netherlands
2
Department of Cardiology,
Rijnland Hospital, Leiderdorp,
The Netherlands
3
Department of Nuclear
Medicine, Medical Center
Alkmaar, Alkmaar,
The Netherlands
4
Department of Cardiology,
VU Medical Center,
Amsterdam, The Netherlands
Correspondence to
Marije MG Krul;
marijekrul@hotmail.com
BMJ Open Diabetes Research and Care 2014;2:000004. doi:10.1136/bmjdrc-2013-000004
Coronary artery disease in patients
with atypical chest pain with and
without diabetes mellitus assessed
with coronary CT angiography
Marije M G Krul,1 Kjell Bogaard,2 Remco J J Knol,3 Albert C van Rossum,4
Paul Knaapen,4 Jan H Cornel,1 Friso M van der Zant3
ABSTRACT
Introduction: Coronary artery disease (CAD) in
diabetes mellitus (DM) is often widespread when
diagnosed. Non-invasive coronary calcium scoring and
coronary CT angiography (CAC-score/CCTA) are
accurate in the detection of CAD. This study compared
CAD characteristics as identified by CCTA between
patients with and without DM with atypical chest pain.
Methods: CAD was defined as CAC-score >0 and/or
presence of coronary plaque. Several CAD
characteristics (number of affected segments,
obstructive (>50% stenosis) CAD and CAD distribution)
were compared on a per patient and segment basis.
Subanalysis of duration of DM (<5 or >5 years) and
gender was performed.
Results: A total of 1148 patients (63.3% men, mean
age 57.7±10.7), of whom 99 (8.6%) suffered from DM,
were referred for CCTA. There was no difference in the
prevalence of CAD between patients with and without
DM (53.5% vs 50.9%, p=0.674). However patients
with DM showed more affected coronary segments
compared with patients without DM (2.5±3.4 vs 1.7
±2.4, p=0.003). Multivariate analysis indicated that DM
was an independent predictor of obstructive CAD (OR
2.16, 95% CI 1.23 to 3.78), as were age, women, and
Diamond-Forrester score. In our study, obstructive CAD
was more prevalent in women than in men (DM 40.0%
vs 14.1%, p=0.003; non-DM 16.8% vs 8.4%,
p<0.001). Patients suffering from DM >5 years showed
more distal plaques (11.2% vs 7.7%, p=0.030).
Conclusions: Patients with atypical chest pain and
DM showed more extensive CAD, as well as more
obstructive CAD, particularly in women. Diabetes
duration (>5 years) was not associated with more
obstructive coronary disease or different plaque
morphology, although more distal disease was present.
INTRODUCTION
The number of people with diabetes mellitus
(DM) is increasing due to population
growth, aging, urbanization, increasing
prevalence of obesity, and physical inactivity,
with an estimated number of 200 million
patients worldwide.1 Patients with DM have a
Research
Key messages
▪ Approximately 50% of middle-aged individuals
with cardiovascular risk factors presenting with
atypical chest pain will have previously undiag-
nosed coronary artery disease (CAD); presence
of diabetes history does not affect this
relationship.
▪ Patients with diabetes mellitus (DM) showed
more affected coronary segments and more
obstructive CAD than patients without DM.
▪ Obstructive CAD was detected more frequently in
women with DM, as compared with men with
DM.
▪ Duration of DM (>5 years) is associated with the
occurrence of distal plaques.
twofold to fourfold likelihood of developing
coronary artery disease (CAD) with marked
morbidity and mortality.2 CAD in patients
with DM is often more advanced at the time
of diagnosis compared with patients without
DM.3 4
Non-invasive cardiac imaging for the detec-
tion of CAD has evolved rapidly in the past
decades. Coronary CT angiography (CCTA)
offers detailed information on the extent
and morphology of CAD. CCTA combined
with coronary calcium scoring (CAC-score) is
sensitive and specific in the detection of
CAD and has been validated extensively.5
The real strength of CCTA is the exclusion of
CAD in patients with a low-to-intermediate
cardiovascular risk profile, and for this par-
ticular indication, there is a broad endorse-
ment from international societies.6 Owing to
technological improvements of CCTA, the
radiation dose per patient has been reduced
to acceptable levels. The latest generation
scanners produce submillisievert (mSv) scans
without compromising image quality.7
The aim of the present study was to
compare characteristics of CAD in patients
1
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Cardiovascular and metabolic risk
with atypical chest pain with and without DM using a
CCTA scanner of the latest generation, and to investigate
the relationship between CAD and the duration of DM.
METHODS
Study design
Consecutive patients with atypical chest pain, referred
for CCTA to exclude CAD at the Medical Center
Alkmaar (MCA) were entered in a database prospect-
ively between December 13, 2011 and March 08, 2013.
Patients were categorized in two groups, either with or
without known DM. Type 1 and 2 DM were included.
DM was diagnosed according to the American Diabetes
Association criteria: fasting glucose level of ≥7 mmol/L,
symptoms of DM and casual plasma glucose of
≥11.1 mmol/L, or the need for oral hypoglycemic
agents or insulin.8 Only patients in sinus rhythm and
without contraindications to CCTA were included. Other
exclusion criteria were a history of CAD, myocardial
infarction (MI), and/or revascularization procedures.
All patients gave written informed consent.
The following patient characteristics were recorded:
general data such as age and gender, a full cardiovascu-
lar risk profile, active medication use, Duke risk score
calculation,9 and the Diamond-Forrester risk score calcu-
lation.10 Positive family history of premature CAD was
defined as the presence of CAD in first-degree relatives
younger than 55 (men) or 65 (women) years of age.11
Smoking was defined as nicotine misuse within the previ-
ous 5 years. Hypertension was defined as a systolic blood
pressure above 140 mm Hg and/or a diastolic blood
pressure above 90 mm Hg or the use of antihypertensive
drugs.12 High cholesterol was defined as a total choles-
terol >5.0 mmol/L or the use of lipid-lowering therapy.13
The duration of DM was categorized in two groups (<5;
>5 years). Furthermore, differences between women and
men were analyzed.
Patient preparation
CCTA was performed under fasting conditions.
Medication could be used normally, with the exception
of metformin (in case estimated glomerular filtration
rate (eGFR) <60 mL/min) and sildenafil. To prevent
contrast-induced nephropathy, patients with an eGFR
between 30 and 60 mL/min received volume expansion
therapy, using 0.9% NaCl intravenously, before and after
CCTA according to the local hospital safety protocol. In
case of a heart rate above 60 bpm, 100 mg atenolol was
given orally 1 h prior to the CCTA. Additionally, up to
30 mg metoprolol was administered intravenously to
decrease the heart rate if the heart rate still exceeded
60 bpm. Each patient also received two doses of 0.4 mg
nitroglycerin sublingually.
CAC-score and CCTA data acquisition
All scans were performed with a dual source 128–slice
(Somatom Definition Flash; Siemens Medical Systems,
2 BMJ Open Diabetes Research and Care 2014;2:000004. doi:10.1136/bmjdrc-2013-000004
Erlangen, Germany). A 10–15 mL test bolus containing
non-ionic low-osmolar iodinated radiocontrast (iopro-
mide) was injected, followed by a flush of 40 mL saline,
both at a flow rate of 6 mL/s. The time point of
maximal contrast enhancement in the ascending aorta
at the level of the pulmonary trunk was recorded, and
an additional delay of 5 s was added to define the
optimal time point for acquisition of coronary artery
data. A dual-head injector then injected 48–75 mL con-
trast depending on kV used for the high-pitch flash scan
and 75 mL in case of prospective or retrospectively trig-
gered scan, followed by 45 mL 30/70% contrast/saline
solution at a flow rate of 6 mL/s.
The tube voltage (80, 100, or 120 kV) and tube
current were determined automatically by the scanning
system based on body geometry.14 In this study, the total
radiation dose of test bolus, topogram, CAC-score, and
CCTA was used to estimate the effective radiation dose
for each patient.
CAC-score and CCTA image analysis
All scans were read by two physicians, who are level 2
accredited by the Society of Computed Cardiovascular
Tomography (SCCT).
For CAC-score, coronary calcifications were defined as
dense lesions in coronary arteries with densities >130
Hounsfield units. Calcifications were manually assigned
to coronary arteries and added to the Agatston score for
each patient.15 Agatston scores were divided into three
groups: a CAC-score between 0–100, 101–400, and more
than 400.
Plaque characteristics were compared on a per patient
and segment basis. Coronary arteries were divided into
18 segments according to the SCCT guidelines.16 Each
segment was scored for the presence of coronary
plaques. Structures >1 mm2 within and/or adjacent to
the coronary artery lumen, which could be clearly distin-
guished from the vessel lumen, were scored as a coron-
ary plaque.17 One coronary plaque was scored per
coronary segment. Each coronary plaque was quantified
for stenosis by visual estimation. The severity of stenosis
was categorized (<25%; 25–49%; 50–69%; 70–99%;
100%). A stenosis of >50% was considered to be
obstructive. The number of coronary segments with non-
obstructive as well as obstructive plaques was determined
for each patient. The morphology of a coronary plaque
was categorized as calcified, non-calcified, or mixed
lesion.
CAD was determined as CAC-score >0 and/or any cor-
onary plaque. CAC-score=0 and no coronary plaques was
defined as no CAD.
To compare the distribution of coronary plaques
between patients with and without DM, patients were
stratified by the location/distribution of atherosclerosis
in either proximal or distal segments. The left main
artery and proximal segments of the left anterior des-
cending (LAD), right coronary artery (RCA), and ramus
circumflexus (RCX) were assigned to the proximal
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Cardiovascular and metabolic risk

Table 1 Baseline, CAC-score and CCTA characteristics of study population with and without DM
Variable DM (n=99) Non-DM (n=1049) p Value
Demographic
Age (years) 58.6±9.9 57.7±10.8 0.435
Sex (% male) 64 (64.6) 663 (63.2) 0.776
Duration of DM (years) 6.6±6.9 0±0
Risk factors
Hypertension 73 (73.7) 676 (64.4) 0.063
Dyslipidemia 86 (86.9) 823 (78.5) 0.049
Obesity (BMI ≥30) 43 (43.4) 188 (17.9) 0.001
Smoking 19 (19.2) 213 (20.3) 0.792
Family history of CAD 53 (53.5) 518 (49.4) 0.429
SBP (mm Hg) 138.8±17.4 133.1±17.2 0.678
DBP(mm Hg) 81.2±12.4 80.7±11.5 0.833
LDL cholesterol (mmol/L) 2.9±1.1 3.6±1.0 0.770
HDL cholesterol (mmol/L) 1.2±0.3 1.4±0.4 0.003
Total cholesterol(mmol/L) 4.9±1.4 5.7±1.1 0.060
HbA1c (mmol/L) 7.2±1.1 5.7±0.4 0.001
Duke score
Low risk 36 (36.4) 599 (57.1) 0.001
Intermediate risk 56 (56.5) 425 (40.5) 0.002
High risk 7 (7.1) 26 (2.4) 0.007
Diamond-Forrester score 39.5±21.6 38.2±22.2 0.562
Medication
ACE-I/ARB 43 (43.4) 238 (22.7) 0.001
Aspirin 41 (41.4) 357 (34.0) 0.140
β-blocker 52 (52.5) 437 (41.7) 0.037
Statin 64 (64.6) 345 (32.9) 0.001
Technical data
Heart rate (bpm) 61.0±7.4 57.1±7.0 0.001
Radiation dose (mSv) 3.8±2.7 2.2±1.8 0.001
CCTA
CAC-score 118±270.7 73.5±209.3 0.049
0–100 74 (74.7) 866 (82.6) 0.057
101–400 19 (19.2) 125 (11.9) 0.037
>400 6 (6.1) 58 (5.5) 0.826
Normal/no plaque 46 (46.5) 515 (49.1) 0.617
CAD 53 (53.5) 534 (50.9) 0.674
Obstructive CAD 23 (23.2) 121 (11.5) 0.001
Non-obstructive CAD 30 (30.3) 413 (39.4) 0.076
Segments
Number of diseased segments 2.5±3.4 1.7±2.4 0.003
Number of segments with obstructive plaques 0.4±1.0 0.2±0.6 0.001
Number of segments with non-obstructive plaques 2.0±2.8 1.5±2.1 0.022
Number of diseased segments LM 0.2±0.4 0.1±0.3 0.114
Number of diseased segments RCA 0.7±1.1 0.4±0.8 0.008
Number of diseased segments LAD 1.1±1.4 0.8±1.1 0.053
Number of diseased segments RCX 0.6±1.0 0.3±0.7 0.001
Categorical variables are expressed as count (%). Continuous variables are expressed as mean±SD.
ARB, angiotensin receptor blocker; BMI, body mass index; CAC-score, coronary calcium score; CAD, coronary artery disease; CCTA, cardiac
CT coronary angiography; DBP, diastolic blood pressure; DM, diabetes mellitus; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein;
LAD, left anterior descending; LDL, low-density lipoprotein; LM, left main; mSv, millisievert; RCA, right coronary artery; RCX, ramus
circumflexus; SBP, systolic blood pressure.

group. Mid and distal segments of LAD, RCA, and RCX
and all evaluable other coronary branches were assigned
to the distal group.
Statistical analysis
Continuous variables are presented as mean±SD and cat-
egorical variables as frequencies with percentages.
One-sample Kolmogorov-Smirnov tests were used to test
continuous data for normal distribution. Between
groups, differences in mean values were tested for statis-
tical differences with two-sample t tests and
Mann-Whitney tests, when appropriate. Pearson χ2 tests
were used to test dichotomous parameters. To deter-
mine the relationship between plaque characteristics

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Cardiovascular and metabolic risk

summarizes the characteristics of patients with and

Table 2 Baseline characteristics of patients with DM with
and without CAD
without DM at the time of the CCTA. In total, 1148
patients (727 (63.3%) men; age (mean 57.7 years±10.7))
DM with DM without were included, of whom 99 (8.6%) were patients with
CAD CAD
known DM (mean 6.6 years±6.9). Of the study popula-
Variable (n=53) (n=46) p Value
tion, 95.4% had a low-to-intermediate probability for
Demographic CAD according to their Duke risk score (92.9% DM vs
Age (years) 62.1±9.2 54.5±9.2 0.718 97.9% non-DM, p=0.007). Patients with DM were more
Sex (% male) 29 (54.7) 35 (76.1) 0.027
frequently obese and used more ACE-I/angiotensin
Duration of DM 7.1±7.4 6.0±6.3 0.468
(years)
receptor blocker, β-blocker, and statin therapy and had
Risk factors lower high-density lipoprotein levels ( p values 0.001,
Hypertension 29 (54.7) 17 (37.0) 0.077 0.001, 0.037, 0.001, and 0.003, respectively). Table 2
Dyslipidemia 50 (94.3) 36 (78.3) 0.018 compares the clinical and radiographic characteristics of
Obesity (BMI ≥30) 20 (37.7) 20 (43.5) 0.220 patients with DM who did or did not have CAD. Patients
Smoking 8 (15.1) 11 (23.9) 0.266 with DM without CAD were more often of the male
Family history of CAD 28 (52.8) 25 (54.3) 0.880 gender, showed less frequent dyslipidemia, and used less
Medication statin therapy ( p values 0.020, 0.018, and 0.046, respect-
ACE-I/ARB 28 (52.8) 15 (32.6) 0.043 ively). None of the other measured clinical variables dif-
Aspirin 26 (49.1) 15 (32.6) 0.098 fered between patients with DM with or without CAD.
β-blocker 30 (56.6) 22 (47.8) 0.383
Statin 39 (73.6) 25 (54.3) 0.046
CAD on CCTA
Technical data
Heart rate (bpm) 59.3±6.6 62.7±8.0 0.849 Coronary plaque characteristics on CCTA in patients
Radiation dose (mSv) 3.6±2.9 4.0±2.6 0.640 with and without DM are shown in table 1. A normal
Categorical variables are expressed as count (%). Continuous CCTA was found in 561 (48.9%) patients, with no signifi-
variables are expressed as mean±SD. cant difference in prevalence between patients with and
ARB, angiotensin receptor blocker; BMI, body mass index; CAD, without DM ( p=0.617). Patients with DM had a signifi-
coronary artery disease; DM, diabetes mellitus; mSv, millisievert.
cantly higher CAC-score than patients without DM (118
±270 vs 73±209, p=0.049). Patients with DM had a signifi-
and DM, logistic regression analyses were performed cantly higher percentage of CAC-scores between 101
when the dependent variable was dichotomous. When and 400 (19% vs 11.9%, p=0.037). Obstructive CAD was
the dependent variable was continuous, linear regres- observed in 144 (12.5%) patients and more frequently
sion analyses were performed. Univariate analyses were in patients with DM (23.2% vs 11.5%, p<0.001). Higher
performed using demographic variables, classical risk CAC-scores were detected in patients with obstructive
factors, risk scoring systems, and medication used (vari- CAD (287.3±332.9 vs 47.2±173.4, p<0.001). The average
ables specified in table 1). Multivariable analyses were number of diseased segments was higher in patients
performed with variables that were significant in univari- with DM compared with patients without DM ( p=0.003).
ate analyses. p Values <0.05 were considered significant. The number of segments with obstructive CAD plaques
The Duke risk score was not analyzed in the univariate was higher in patients with DM compared with patients
and multivariate analyses because DM is one of the para- without DM. In patients with DM, the average number
meters in this particular score. The Diamond-Forrester of diseased segments in the RCA ( p=0.008) and RCX
score, not using DM as a parameter, was used instead. ( p<0.001) was higher than in patients without DM. The
For the detailed per segment analysis, the unit of difference in the average amount of diseased segments
measure was each coronary segment and there were no in the LAD did not reach statistical significance
adjustments or corrections made for the serial correl- ( p=0.053).
ation between segments. Statistical Package for Social Figure 1 shows the prevalence of obstructive CAD
Sciences V.20 (SPSS Inc, Chicago, Illinois, USA) was across the subgroup gender. Women had an overall
used. higher prevalence of obstructive CAD than men. In
patients with DM, 40% of the women demonstrated
obstructive CAD compared with 14.1% of the men
RESULTS ( p=0.003). In patients without DM, 16.8% of the women
Study population compared with 8.4% of the men showed obstructive
A total of 1176 patients with atypical chest pain were CAD ( p<0.001).
enrolled in the study, of which 28 patients were
excluded. Twenty-three patients were excluded due to a Relationship of CAD characteristics on CCTA and DM
history of CAD, MI, and/or revascularization proce- The results of the univariate and mulitivariate analyses
dures. Five patients suffered from arrhythmias during of the correlation between plaque characteristics on
scan acquisition which resulted in unacceptable image CCTA and the presence of DM are listed in table 3.
quality, and thus, these patients were excluded. Table 1 After correction for baseline characteristics, DM proved

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Cardiovascular and metabolic risk

remaining 17 135 segments, 1998 (11.7%) segments

contained plaque. Of the 17 135 segments, there were
243 (1.4%) segments with obstructive plaque, (44 of
1471 (3.0%) segments in patients with DM, 199 of
15 664 (1.3%) in patients without DM, p<0.001).
Accordingly, the distribution of plaque types differed
between DM and non-DM: mixed plaques (13.3% vs
9.2%, p<0.001), calcified plaques (2.0% vs 1.3%,
p=0.015), and non-calcified plaques (1.4% vs 0.8%,
p=0.023). Patients with DM showed significantly more
affected segments than patients without DM in the RCA
(4.4% vs 2.7%, p<0.001), LAD (7.3% vs 5.6%, p=0.012),
and RCX (3.8% vs 2.1%, p<0.001).

Figure 1 Prevalence of obstructive coronary artery disease
(CAD) across the different diabetes mellitus and gender
subgroups.
to be an independent predictor of the total number of
segments with plaque ( p=0.016). The other independ-
ent predictors of the total number of segments with
plaque were age ( p<0.001), women ( p<0.001),
Diamond-Forrester score ( p<0.001), and hypertension
( p=0.023). Furthermore, DM was an independent pre-
dictor of the presence of obstructive plaque (OR 2.16,
95% CI 1.23 to 3.78), as were age (OR 1.04; 95% CI
1.02 to 1.07), women (OR 4.95; 95% CI 2.96 to 8.28),
and Diamond-Forrester score (OR 1.02; 95% CI 1.00 to
1.03). DM was also an independent predictor of the
number of segments with plaque in the distal segments
( p=0.010), as were age ( p<0.001), women ( p<0.001),
and Diamond-Forrester score ( p=0.008).
Per segment analysis
A total of 17 240 segments were identified in the study
population. After exclusion of 105 (0.61%) segments
due to non-diagnostic image quality, a total of 17 135
coronary segments were included in the analysis. In the
Subgroup analysis for duration of DM
Table 4 shows the subgroup analysis for duration of DM
in the per segment analysis. Duration of DM was categor-
ized into two groups (<5; >5 years). Although patients
suffering from DM for more than 5 years had a higher
percentage of involvement of the distal segments (11.2%
vs 7.8%, p=0.030), duration of diabetes had minimal
impact on total number of segments with plaque,
number of obstructive lesions, and morphology of
plaques.
DISCUSSION
In the present study, differences in characteristics of
CAD between patients with and without DM were
detected by means of CCTA. A significant, positive cor-
relation between the presence of DM and total number
of segments with plaque was demonstrated. Patients with
DM had a significantly higher percentage of obstructive
plaques, and this was particularly true for women.
Patients suffering from DM for more than 5 years did
not demonstrate more obstructive coronary disease or
different plaque morphology, although more distal
disease was present.

Table 3 Estimates of correlation of CCTA plaque characteristics with the presence of DM

Variable Univariate, parameter estimate p Value Multivariate, parameter estimate p Value
Total calcium score 22.25 0.049 16.88 0.127
Total segments with plaque 0.394 0.003 0.292 0.016
CAD 1.11 (0.74 to 1.70) 0.617
Obstructive plaque 2.32 (1.40 to 3.84) 0.001 2.16 (1.23 to 3.78) 0.007
Non-obstructive plaque 0.67 (0.43 to 1.05) 0.078
LM (yes or no) 1.54 (0.90 to 2.70) 0.107
RCA (yes or no) 1.45 (0.93 to 2.60) 0.101
LAD (yes or no) 1.22 (0.81 to 1.85) 0.337
RCX (yes or no) 1.59 (1.01 to 2.49) 0.044 1.36 (0.82 to 2.26) 0.229
Proximal plaques 0.142 0.019 0.089 0.110
Distal plaques 0.253 0.002 0.203 0.010
Data are ORs (95% CI) or estimates of correlation.
CAD, coronary artery disease; CCTA, cardiac CT coronary angiography; DM, diabetes mellitus; LAD, left anterior descending; LM, left main;
RCA, right coronary artery; RCX, ramus circumflexus.

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prevalence of CAD in asymptomatic patients with DM.

Table 4 Prevalence, extent, localization, and morphology of
plaques—per segment analysis in subgroup duration of DM
The total CAC-score was significantly higher in patients
with DM than in patients without DM ( p<0.001). Higher
DM <5 years DM >5 years CAC-scores were present in patients with obstructive
(n=53; 797 (n=46; 683
CAD.23 In an earlier study, Rivera et al24 also demon-
segments) segments) p Value
strated an increasing prevalence of significant stenoses
Total segments 790 (99.1) 681 (99.7) 0.149 with increasing CAC-scores ( p<0.001).
Total segments 121 (15.3) 125 (18.4) 0.108 The present study showed that many patients with DM
with plaque
already developed serious CAD at the time of examin-
Obstructive 23 (2.9) 21 (3.1) 0.847
plaque
ation. One explanation could be that DM had existed
Non-obstructive 98 (12.4) 104 (15.3) 0.111 long before it was diagnosed, due to lack of typical symp-
plaque toms of the disease, and cardiovascular damage could
Plaque in LM 12 (1.5) 6 (0.9) 0.267 have developed meanwhile.4 The previously mentioned
Plaque in RCA 32 (4.1) 32 (4.7) 0.544 studies demonstrated this in asymptomatic patients with
Plaque in LAD 53 (6.7) 55 (8.1) 0.316 DM.
Plaque in RCX 24 (3.0) 32 (4.7) 0.097 Furthermore, in the present study women had a
Proximal plaque 59 (7.5) 49 (7.2) 0.841 higher percentage of obstructive CAD in the DM and
Distal plaque 62 (7.8) 76 (11.2) 0.030 non-DM group. This is in contrast with several previous
Mixed plaque 96 (12.2) 99 (14.5) 0.179 studies with CCTA that showed more obstructive CAD in
Calcified plaque 15 (1.9) 15 (2.2) 0.681
men.21 25 These apparently conflicting results might be
Non-calcified 10 (1.3) 11 (1.6) 0.573
explained by the increasing notion of, and attention to,
plaque
the atypical and late presentation of cardiac symptoms
Categorical variables are expressed as count (%).
DM, diabetes mellitus; LAD, left anterior descending; LM, left in women.26 27 On average, clinical symptoms of heart
main; RCA, right coronary artery; RCX, ramus circumflexus. disease appear 10 years later in women than in men.26
Studies in the Women’s Ischemia Syndrome Evaluation
(WISE) study support the concept of a multifactorial
Extent of CAD model where sex hormones interact with traditional and
The present study showed a positive correlation between novel risk factors. Especially inflammatory process bio-
the presence of DM and the total number of segments markers (such as C reactive protein), leading to an
with plaque. Patients with DM showed more affected seg- increase in the functional expression of atherosclerotic
ments than patients without DM. Higher prevalence of plaque and vascular or metabolic alterations result in
plaques in patients with DM has been reported in previ- worse outcomes for women.28 Also, medical diagnosis
ous invasive as well as postmortem studies. Pundziute and treatment for stable angina is different in men and
et al18 reported observations in 60 patients (including 19 women.29 Women were less likely to be referred for
with DM) using CCTA followed by conventional coron- testing, in particular for exercise testing and invasive
ary angiography with intravascular ultrasound (IVUS); angiography. Antiplatelet and statin therapies were used
the authors demonstrated that patients with DM had sig- significantly less in women than in men at the initial
nificantly more affected segments on CCTA and with assessment and at 1 year, even in those in whom CAD
IVUS. In a postmortem study, Burke et al19 showed that had been confirmed, which unfortunately influences
patients with DM have a larger amount of total and outcome.
distal plaques. In our study, in patients with atypical
chest pain, DM was also associated with more obstructive Duration of DM
CAD. This is in line with an earlier study performed by Previous studies have shown that the duration of type 2
Chu et al20 who demonstrated more obstructive plaques DM correlates with all-cause mortality and significantly
in symptomatic patients with DM as compared with increases cardiovascular mortality.30 31 An autopsy study
patients without DM (2.5±2.5 vs 1.1±1.4). The CAC-score demonstrated an association between DM duration and
in our study was higher in patients with DM, compared the extent of atherosclerosis and myocardial lesions.32
with patients without DM (118±270.7 vs 73.5±209.3, Clarkson et al33 showed that vascular reactivity, a marker
p=0.049). This is in line with an earlier study by de of impaired endothelial dysfunction, is impaired in
Araujo et al21, who showed a significant difference in patients with long-term type 1 DM. Also the degree of
(median) CAC-score between patients with atypical chest impairment is related to the duration of DM. Thus, one
pain with and without DM (68(0–311) vs 0 (0–67), may speculate that longer exposure to hyperglycemia
p<0.001). While our study looked at CAD in patients may increase the risk of endothelial dysfunction and
with atypical chest pain and DM, several studies have thus increase the risk of developing CAD. To the best of
demonstrated CAD in asymptomatic patients with DM. our knowledge, no studies researched the correlation
Scholte et al22 revealed a high prevalence of CAD in between the duration of DM and distal plaques. In our
asymptomatic patients with type 2 DM, with almost 80% study, we found that patients suffering from DM for
showing CAD. Zeina et al also showed a higher more than 5 years have more distal plaques, although

6 BMJ Open Diabetes Research and Care 2014;2:000004. doi:10.1136/bmjdrc-2013-000004

 Downloaded from http://drc.bmj.com/ on October 23, 2014 - Published by group.bmj.com
they did not demonstrate more obstructive coronary
disease or different plaque morphology. Patients suffer-
ing from DM for a prolonged period will have more
extensive and widespread disease.
Radiation dose CCTA
Bell et al34 showed in a prospective study that iodinated
contrast, β-blockers, and nitroglycerin as part of a prede-
fined CCTA protocol are safe and associated with a low
rate of adverse events. In the past decade, studies have
focused on radiation dose-reduction techniques with
CCTA. The latest generation CCTA scanners can provide
an effective dose below 1.0 mSv.7 In comparison, patient
dose is typically 2.4 mSv for a 13NH3 positron emission
tomography scan, 2.5–5 mSv for diagnostic invasive
selective coronary angiography, and 5–16 mSv for
nuclear myocardial perfusion imaging by means of
single photon emission CT.35–37 Safety and low radiation
exposure with a high negative predictive value makes
CCTA a very appropriate imaging technique for the
exclusion of CAD in symptomatic patients and perhaps
even as a presymptomatic screening tool. The radiation
dose of CCTA in this study is higher in patients with DM
compared with patients without DM. This difference
could be explained by the fact that patients with DM are
more obese compared with patients without DM. Obese
patients require a higher tube voltage (kV) and current
(mAs) to produce a diagnostic CCTA, which leads to a
higher radiation dose.
Clinical implication
The combination of CAD and DM strongly increases car-
diovascular mortality.30 31 The present study showed that
a clinically significant number of patients with atypical
chest pain and DM already had developed (serious)
CAD at the time of first examination. Previous studies
with asymptomatic patients also demonstrated a higher
prevalence (80–93%) of CAD in patients with DM.22–23
There is extensive evidence of prognostic information
using CAC-score in symptomatic and asymptomatic
patients.38 However, the additional value of performing
CCTA in these patients has been a matter of debate. In
the CONFIRM registry, CCTA was unable to predict
death of non-fatal MI in 7500 patients.39 Nonetheless, in
symptomatic patients the incremental prognostic value
of CCTA has been established.40 The best CCTA param-
eter for prediction of mortality was the number of prox-
imal segments with mixed or calcified plaques.41 Thus,
CCTA is useful in detection of CAD in patients with DM,
either with or without symptoms of atypical chest pain.
The high diagnostic yield in symptomatic patients with
DM may justify the use of CCTA in daily clinical practice
and can be considered as a criterion for appropriate
use. Since prognostic value of performing CCTA in
asymptomatic patients is unclear, further prospective
studies are needed.
BMJ Open Diabetes Research and Care 2014;2:000004. doi:10.1136/bmjdrc-2013-000004
Cardiovascular and metabolic risk
Limitations
Several limitations should be mentioned. First, this is a
single-center study with a medium-size cohort in which
the percentage of patients with DM was relatively small.
Also, the examinations were performed at a single time
point. There were some differences in the baseline
characteristics of the two subgroups of patients, like
obesity, and medication use, that could have contributed
to the higher disease extent observed in patients with
DM. Nevertheless, after adjusting for those differences,
DM remained an independent predictor of plaque
burden and obstructive CAD. Since patients referred for
CCTA were suffering from atypical chest pain, but had
no history of clinically diagnosed CAD, a potential refer-
ral bias has to be taken into account. In addition, limita-
tions of CCTA in general should be mentioned; the
presence of ischemia cannot be determined on CCTA,
and abnormal CCTA findings should ideally be com-
bined with functional data.
CONCLUSIONS
Although the prevalence of CAD in patients with atyp-
ical chest pain and DM did not differ from that in
non-DM, patients with DM with CAD had more
advanced CAD than patients without DM. They showed
more affected coronary segments and more obstructive
CAD than patients without DM; the latter especially in
women with DM. Duration of DM (>5 years), in our
study population, was not associated with more obstruct-
ive coronary disease or a different plaque morphology,
although more distal disease was present.
Contributors MMGK and KB researched data and wrote the manuscript. RJJK
researched data and reviewed/edited the manuscript. ACvR reviewed/edited
the manuscript. PK and JHC contributed to the discussion and reviewed/
edited the manuscript. FMvdZ researched data, contributed to the discussion,
and reviewed/edited the manuscript
Funding This research received no specific grant from any funding agency in
the public, commercial or not-for-profit sectors.
Competing interests None.
Ethics approval The patients were prospectively included in the study and all
patients signed informed consent. All patients did sign an informed consent
for usage of their data.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/3.0/
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 Downloaded from http://drc.bmj.com/ on October 23, 2014 - Published by group.bmj.com

Coronary artery disease in patients with

atypical chest pain with and without diabetes
mellitus assessed with coronary CT
angiography
Marije M G Krul, Kjell Bogaard, Remco J J Knol, Albert C van Rossum,
Paul Knaapen, Jan H Cornel and Friso M van der Zant

BMJ Open Diab Res Care 2014 2:

doi: 10.1136/bmjdrc-2013-000004

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